The present invention relates to a method for preparing enteric-coated oral drugs containing acid-unstable compounds, in particular an enteric-coated oral drug prepared in the form of acid-stable dosage units as inclusion complex formed by reacting benzimidazole derivative, acid-unstable compound, with cyclodextrin in alkaline solution.
Acid-unstable compounds, especially the benzimidazole compounds, are easily discolored and degraded under acidic and neutral conditions. For example, omeprazole, a benzimidazole derivative, has half-life of 10 minutes in medium of below pH 4, but 18 hours at pH 6.8 and about 300 days at pH 11. Omeprazole has been reported to be stable in alkaline condition [Pilbrant A and Cederberg C. Scand. J. Gastroenterology, Suppl. 108, 113-120(1985)]. The acid-unstable compounds when exposed to the environment also get discolored and degraded by getting in contact with moisture and organic solvents.
Therapeutic use of the acid-unstable compounds which inhibit gastric acid secretion and are used to cure peptic ulcer and/or duodenal ulcer, requires apprepriate mechanism to protect these compounds from degradation in gastric juice after oral administration.
Methods for stabilizing the acid-unstable compound, in particular omeprazole has been known to be as follows; Omeprazole is combined with alkaline salt such as Na.sup.+, K.sup.+, Mg.sup.+2, Ca.sup.+2 and so on to maintain the stability for compound itself. PCT Publication No. 86-00913(PCT/EP 85/00371 ) discloses to form a stable complex by mixing and reacting omeprazole with .beta.-cyclodextrin in 96% ethanol and cooling the reactant.
The latter process seems to have the problem as the reaction is conducted at a temperature 25.degree..about.38.degree. C. for 15 hours in ethanol, during the reaction itself omeprazole can get discolored and degraded. Furthermore, it is difficult to expect the formation of inclusion compound because both omeprazole and cyclodextrin are dispersed in the reaction as solid particles, not dissolved. For forming an inclusion compound of cyclodextrin, the reaction must be carried out in presence of water molecules [K. Hara, H. Hashimoto, J. Jpn. Soc. Starch. Sci., 32(2) 152-161(1986)]. Therefore, the latter method not expected to give inclusion compound since the above reacting condition has not been considered.
On the other hand, Unexamined Korean Patent No. 87-9718 and Korean Patent Publication No. 91-4579 disclose processes for preparing omeprazole preparation consisting of mixing omeprazole with alkaline substance to form core material, forming a watersoluble internal layer on the core and forming an enteric coating to stabilize omeprazole.
It has, however, been found that the stabilizing methods known in the Korean Patents have several problems as followings; The process for preparing core material and forming enteric-coating is very complicated. The stabilized omeprazole is discolored and degraded during stay in stomach after oral administration, because gastric juice passes through the enteric-coating to partially dissolve the watersoluble internal layer and then infiltrated into the core to dissolve the alkaline substance partially destroying the enteric-coating. The stability of omeprazole by this process is not secured concretely. For formulating omeprazole, it is necessary to give good attention to omeprazole itself. For example, it must be kept at below -20.degree. C. of low temperature and immediately used for formulating after removing moisture, or immediately after synthesis, to maintain the starting stability.
After all, tier stabilizing the acid-unstable compound a primary factor is not only to secure the stability of preparation but also to stabilize the compound itself. Thus the attempt to stabilize acid-unstable compound must take into account the stability of the compound during the stablization process, its stability against gastric juice and the need to quickly and completely dissolve are made the available main drug for absorption in the intestine.
As discussed above most of the previously described methods are either very partially successful in stabilization or the stable inclusion compound is not produced at all conjugation attempt to add alkaline salt to omeprazole have also been unsatisfactory.